AU782251B2 - Tissue sensitizing compounds for females with methods and apparatus for the delivery of these compounds - Google Patents

Description

WO 01/45599 PCT/US00/33987 -l- Tissue Sensitizing Compounds for Females with Methods and Apparatus for the Delivery of these Compounds Background of the Invention Field of the Invention This invention relates to arrangements for the stimulation of female tissue and more particularly to topical application of specialized stimulatory medicaments for the lips or the clitoris of human females.

Prior Art The unique properties of the clitoral sensitizing compounds encompasses the vasodilatation of clitoral blood vessels by the initial effect of menthol to facilitate and promote the absorption of L-arginine when topically applied to the mucous membrane of the clitoris. The L-arginine stimulates the nitric oxide synthase mediated production of nitric oxide to effect clitoral sensitivity, arousal, and erection by sustained vasodilatation. Both of these actions are specific to the topical application of the compound to the mucous membrane of the clitoris and presume an inert, non-active base or vehicle. In the menthol/L-arginine compound, the menthol actually acts as a vehicle to enhance the absorption of L-arginine.

In the human female, decreased clitoral sensitivity and responsiveness are related to normal aging, relative or absolute estrogen and testosterone deficiency (either as a consequence of medicines or aging), and by a host of vascular conditions such as diabetes and hypertension. Multiple laboratory and clinical research endeavors have been directed toward male erectile dysfunction (ED), yielding not only an understanding of the erection physiology, but also medications to treat ED, such as Viagra

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Very little research has been initiated to understand or address female physiological sexual unresponsiveness. H-lowever, since the penis and the clitoris are analogous anatomical structures, the basic cellular and physiological knowledge about male penile erections translates to functions of the Female clitoral dysfunction is extremely difficult to document and quantify. A number of modalities, such as Doppler blood flow, precise temperature measurements, and actual imaging measurements, have been employed to attempt to WO 01/45599 PCT/US00/33987 -2define clitoral responsiveness all with results unsatisfactory for meaningful research. Estimates that 15 million U.S. men suffer from erectile dysfunction have been reported in the literature. A recent article in the February 10, 1999 issue of the Journal of the American Medical Association suggests that female erectile dysfunction occurs probably twice the rate of male ED, therefore affecting million U.S. women.

In the female anatomy, the clitoral artery is located in the middle of the clitoris, extending lengthwise from the base to the tip of the clitoris, and supplies blood to the clitoris. Two clitoral veins are located on either side of the clitoral artery, and normally drain the clitoris of the blood pumped into it from the artery. As female sexual arousal initiates, either by direct stimulation of the clitoris or by the application of one of the recently developed female arousal creams, the vessels dilate and the valves of the clitoral veins located at the base of the clitoris close. The venous blood fills two honeycomb-like chambers, the corpus cavernosa.

The corpus cavernosa are normally empty of blood, but, like the clitoral artery and veins, they are positioned lengthwise from the base to the tip of the clitoris.

Therefore, as the valves in the veins at the base of the clitoris close, the blood pumped into the clitoris artery distends the corpus cavernosa. This causes the clitoris to enlarge two-to-three fold, and to become erect, rigid, and highly sensitive, just as the penis in the male. In fact, the penis and the clitoris are the exact same structures. Female clitoral enlargement and rigidity and male penile erection are both accomplished by the same action: vasodilation of the vascular structures maximally distending the corpus cavernosa.

Topical application of medications to different types of Integument (skin) to effect changes in sensation are based upon that type of integument. There are two types of integument (skin): keratinized stratified squamous epithelium, and non-keratinized stratified squamous epithelium, more commonly referred to as mucous membrane. The entire external surface of the body is covered with keratinized stratified squamous epithelium except the lips, mouth, anus, and the vagina/vulva in females. If a lotion is applied to the keratinized squamous epithelium, it is absorbed only by the top layers of the skin. Multiple transdermal medications are delivered through the keratinized skin, but the delivery system is WO 01/45599 PCT/US00/33987 -3very sophisticated. Absorption of medications is much easier if they are delivered to mucous membranes, or non-keratinized stratified squamous epithelium, especially the lips, the vulva and vaginal mucosa. Many vaginal creams and suppositories that dissolve to become creams with the moisture and heat of the vagina have been sold for over fifty years. All of the vaginal creams and suppositories are absorbed into full thickness of the non-keratinized stratified squamous epithelium that defines the vaginal mucosa. Some of the vaginal creams are systemically absorbed by the blood vessels in the basement membrane of the vaginal mucosa, while other medications are not systemically absorbed. Systemic absorption refers to the distribution of the medication throughout all tissues of the body via the blood stream. The vaginal/vulvar mucosa is a multiple layer of non-keratinized stratified squamous epithelial cells twenty-to-thirty cells in thickness from the basement membrane to the outermost cells of the mucosa.

The integument of the undercarriage of the clitoris is non-keratinized stratified squamous epithelium (mucous membrane), and topical medications are readily absorbed. The clitoral hood that covers the dorsal aspect of the clitoris is partially keratinized, and allows partial absorption of topical medications. The integument of the penis is keratinized stratified squamous epithelium. Absorption of the same medication topically applied to the penis and the clitoris concurrently will be much more readily absorbed by the clitoris because of the mucous membrane of the clitoris.

Topical menthol is a particular tissue or clitoral sensitizing agent and may be applied to clitoral tissue and may have a number of effects. The specific effects that menthol causes are dependent upon three variables: the concentration of the menthol in the preparation, the vehicle and its evaporation properties, and most importantly, the type of tissue to which the menthol is applied. If the menthol is in a non-evaporating vehicle and applied to keratinized stratified squamous epithelium (hairy skin), a low concentration is under a mid-range concentration, and a high onceiiiiaiiona, .betwee 5% d, 10. If menthol in a non-evanrating vehicle is applied to non-keratinized stratified squamous epithelium (mucous membrane), a low concentration is less than a mid-range concentration between 0.5% and and a high concentration between 2% and Therefore, a WO 01/45599 PCT/US00/33987 -4- 1% concentration of menthol in a non-evaporating vehicle applied to keratinized and non-keratinized epithelium would produce very different effects: the keratinized epithelium would respond with a minimal effect, while the non-keratinized epithelium would respond with a marked effect. This is because of the rapid absorption through the non-keratinized epithelium (mucous membrane) and the relatively poor absorption through the barrier-like keratinized epithelium (hairy skin).

Menthol is highly lipid-soluble and readily absorbed by a mucous membrane. A mid-range concentration of 0.5% to 2% of menthol topically applied to mucous membrane causes almost immediate smooth muscle relaxation, hyperemia, and vasodilation of blood vessels by a direct response. Menthol also causes the immediate stimulation of both thermoreceptors and nociceptors. The thermorcceptors, when stimulated, create a sensation of warmth and burning for this menthol concentration in mucous membrane (like the clitoris). The nociceptors initiate an axon reflex to release vasodilator peptides. The vasodilator peptides cause an immediate vasodilation of blood vessels with resultant blood engorgement and transudate production. The sera component of the blood that leaks out of the blood vessels to provide increased vaginal/vulvar lubrication is due to the nociceptor initiated vasodilation. The onset of all of these mechanisms occurs within thirty seconds of application of the menthol preparation, and these responses persist for fifteen-to-twenty minutes. Therefore, the topical application of a 1% menthol preparation, in a non-evaporating vehicle directly to the mucous membrane of the clitoris, causes the following physiological responses: a. warmth, tingling, and even mild burning; b. hyperemia; c. direct smooth muscle relaxation; d. indirect blood engorgement via nociceptor-mediated vasodilation by peptide release; and e.

increased vulvar/vaginal lubrication.

Topical L-arginine is a clitoral sensitizing agent, produced from intracellular nitric acid which is a potent vasodilator of smooth muscles, and has been identified and confirmed by a number of research studies to be pivotally involved in penile/clitoral erections. Nitric oxide is synthesized from the substrate L-arginine in a cellular reaction catalyzed by nitric oxide synthase (NOS). Two different types of NOS have been identified: eNOS and nNOS. The eNOS is WO 01/45599 PCT/US00/33987 contained with the smooth muscle endothelial cells that line the vasculature of the penis/clitoris. As the available L-arginine is concerted into NO by eNOS, the blood vessels and corpus cavernosa of the penis/clitoris dilate and fill with blood. This engorgement of the penis/clitoris is the mechanism for the erection and rigidity of the aroused penis/clitoris. The nNOS is contained within the nerve cells of the penis/clitoris and converts L-arginine into NO to sensitize the penis/clitoris and cause the release of vasodilation peptide. Burett, et al. reported in "Immunohistochemical Description of Nitric Oxide Synthase Isoforms in Human Clitoris", Journal of Urology, July 1997, 75-79, that the vascular and neuronal alteration of the penis/clitoris that create an erection are the direct effect of the ability of the cells to convert the available L-arginine into nitric oxide through nitric oxide synthase.

Several urologic and gynecologic reports have identified a correlation between a decreased availability or activity of the NO synthase system and normal aging, testosterone deficiency, and estrogen deficiency. The studies confirm that an increase in the supply of the substrate L-arginine allows the attenuated but still functional NOS system to affect the nitric oxide medicated erection of the penis/clitoris. Therefore, the topical application of L-arginine via the NOS system causes vasodilation of the penile/clitoral veinous structures and concomitant sensitivity. The safety of 1% of 2% menthol topically applied to tissue such as the clitoris is a consideration. Two different strengths of menthol may be commercialized, such as 1% and 2% concentrations in a non-evaporating water base. The anticipated normal volume of such cream to be applied to the clitoris is 300 mg. Therefore, the maximum amount of menthol delivered is 6 mg. The Extra Pharmacopoeia, Martindale, 1989, reports menthol toxicity for humans at 28 mg./kg. In a 50 kg individual, the toxic dose could be 1400 mg., but this is estimated to be extremely low by Eccles in his "Review: Menthol and Other Cooling Compounds" in the 1994 Journal of Pharmacological Pharmacopedia, volume 46, pages 618-630. A 6 mg. de of mnthol 1i wvll below the 1400 me.

dose calculated and gives a 100 plus fold margin of safety.

The safety of L-arginine topically applied to tissue such as the clitoris is also a consideration. Two different strengths of L-arginine USP, 2% and 4%, WO 01/45599 PCT/US00/33987 -6may be marketed so as to sensitize the clitoris. The anticipated normal volume of such cream to be applied to the clitoris is 300 mg. Therefore, a maximum of 12 mg. of L-argininc USP is available. If all 12 mg. are systemically absorbed, this is a small fraction of what has been reported in the gynecologic literature as safe.

Fracchinette, et al., reported the intravenous infusion of 30 grams (30,000 milligrams) of L-arginine into 29 pregnant patients without adverse effects in the 1999 Journal of the Society of Gynecologic Investigation, volume 6,202-207.

Brief Summary of the Invention The present invention relates to alternate preparations of menthol and related cooling compounds that comprises a class of single-source of botanical or essential oils that can be used individually or as a combination of several oils such as: Peppermint oil; Cormint oil; Eucalyptus oil; Citronella oil; Indian turpentine oil; Camphor oil and Cinnamon oil.

In fact, all of the botanicals listed by Steinberg in "Frequency Use of Botanicals," in Cosmetics and Toiletries magazine, Volume 113, October, 1998, (incorporated herein by reference) arc members of this class of single-source botanical or essential oils. Potentially, any of these referenced oils could evoke the menthol-like effect on the mucous membrane to facilitate or promote the topical absorption of L-arginine. In addition, known minor skin irritants can cause a profound reaction when topically applied to mucous membrane, such as redness, irritation, and reflex vasodilatation. This irritant reaction associated with vasodilatation shares some similarities with the menthol effect, and could quite effectively substitute for the menthol in promoting L-arginine absorption and actions. Salicylate and capsiatin are two of the commonly used minor skin irritants.

Oil soluble vitamins (coenzymes) A, D, or E, could also potentiate absorption of menthol, L-arginine, minor skin irritants, or any of the menthol-related cooling compounds. The oil soluble vitamins could be used to substitute for, or be used in addition to, any of the previously listed components in a topical clitoral sensitizing preparation.

The invention may further comprise alternate preparations for the base or the vehicle. Such biologically active agents (menthol or its substitutes) and L-arginine can be compounded in a non-biologically active base, or in a biologically WO 01 /45599 PCT/US00/33987 -7active base that promotes absorption, a vehicle. Any base or vehicle is intended to liquefy at body heat and in the presence of moisture present in mucous membrane when topically applied to mucous membrane tissue. Campos and Eccleston is "Vitamin A Skin Penetration", "Cosmetics and Toiletries magazine, volume 113, July, 1998, describe and quantify how different vehicles influence and promote the hairy skin (keratinized stratified squamous epithelium) absorption of Vitamin A.

Mucous membranes absorb solutions more readily than hairy skin, but display linear absorption potentials relative to the vehicles studies by Campos and Eccleston. An active vehicle may be engineered that synergistically functions to promote the absorption and actions of menthol, menthol-related compounds, biologically derived oils, minor skin irritants, oil soluble vitamins, L-arginine, or any combination of these.

There are solid/liquid state dynamics for the topical delivery of clitoral sensitizing compounds which cover any of the potential compounds for topical application to sensitize tissues such as the clitoris because they can have different solid/liquid states at ambient and at body temperatures. A solid compound, such as exemplified by the Chap Stick® Lip Balm, A. H. Robbins Company, of Richmond, Virginia, could be directly applied to the undercarriage of the clitoris, and liquefy at body temperature and in the moisture inherent in mucous membrane tissue. Liquefied compounds are readily absorbed, dependent on various other factors described. A gel/cream or liquid compound could be directly applied to the clitoris for topical absorption. Like the solid-state compound, the gel/cream must liquefy before absorption can be effected. The dynamics of how rapidly a compound transforms from a solid state or gel/cream state to a liquid state could be controlled to evoke an almost immediate effect, or a relatively delayed effect, before absorption of the compound.

A crystalline related dissolution may be different from the temperature related dissolution of a solid or a gel/cream. Small crystals of menthol, SL;-ag;i r nf the nre.vinllqlv described components, may be suspended in a base vehicle. Their availability for absorption would depend on their dissolution from a crystalline state to a liquid state. The crystalline effect may be designed to control the rate of absorption: for instance, whether the compound were available WO 01145599 PCT/US00/33987 -8for absorption immediately on application, or if a delayed, sustained absorption over a period of time were desired. Both of these parameters could allow the discrete, private application of the clitoral-sensitizing compound in anticipation of intercourse, without knowledge of the partner.

Because the clitoral-sensitizing compounds are also intended to function independently without the preferred intercourse-related physical stimulation of the clitoris, the mentholL-arginine compounds may also be arranged to be available in various strength to address the needs of all women. The menthol may be compounded in multiple strengths, ranging from 0.1% to and any increment in between. The L-arginine may also be compounded in multiple strengths ranging from 1% to 10%. The spectrum of different strengths may be compounded into a single delivery system, such as lip balm, or alternatively, in all of the potential delivery systems: solid, gel/cream, and liquid.

A single use or a multiple use delivery systems comprising clitoralsensitizing preparations may be individually packaged within a small tube or packet for single use. Conversely, a multiple-dose reusable delivery system, like a tube of hand cream or toothpaste, or a stick of lip balm, may be packaged for personal use.

The apparatus and methods to deliver a topical preparation to the lips or the clitoris may be comprised of a solid or semi-solid compound that may be directly applied to the undercarriage of the clitoris regardless of the use of a single-or multiple-use delivery system. The clitoral contact area of the solid or semi-solid compound in one preferred embodiment will have a notch to increase the surface area and clitoral contact of the compound. The notch is arranged with a height of 0.5 to 2 centimeters, and a maximum width of 2 centimeters at the rim of the notch. A properly designed concave notch will topically apply the compound to the 180 degree undercarriage of the clitoris. With proper directions for use, the application surface will initially contact the vestibular tissue at the base of the clitoris, to spread the compound on the entire clitoris.

A gelcream or liquid compound would be applied to the tissue or clitoris with the same motions, but would require a different type of application device. The gel/cream or liquid could be applied by "roller balls" like those used to apply viscous deodorants, by a sponge-type applicator, or by a brush type of system.

WO 01/45599 PCT/US00O/33987 -9- Any of the delivery devices for gel/cream or liquids could be designed to increase the surface area of the applicator tip and generally use the concave notch described for the solid compounds. The gel/cream and liquid applicators would have either a single-use reservoir or a multi-use reservoir. All of the delivery devices would have a cap that would seal the device before the initial use, and protect the applicator tip from contamination before use. Multi-use devices would have a resealing cap.

The invention thus comprises a hand-manipulable, tissue or clitoral stimulant-applying applicator for use to apply a clitoral stimulating compound to the clitoral area of the human female, comprising: a reservoir for containment of a clitoral stimulating compound; a clitoral stimulating compound in said reservoir; and a removable cover on the reservoir to expose the compound to permit said compound to be applied topically. The cover may comprise a removable cap. The reservoir may comprise a tube and said cover. The compound may comprise a gel.

The compound may comprise a cream. The compound may comprise a fluid liquid.

The compound may comprise a semi-solid. The semi-solid compound may have a notch on its distalmost end to facilitate the application of the compound. The applicator may include a brush thereon. The applicator may include a sponge thereon. The applicator may include a roller ball arrangement thereon. The compound may be comprised of a mixture of menthol and L-arginine. The compound may have components selected from the group consisting of: Peppermint oil, Cornmint oil, Eucalyptus oil, Citronella oil, Indian turpentine oil, Camphor oil and Cinnamon oils. The compound may have components selected from the group consisting of: Salicylate, capsiatin, and oil soluble vitamins (co-enzymes) of A, D, or E.

The invention may also include a method of sensitizing the tissue or clitoris of a human female, comprising the steps of: applying a compound of sensitizing agent to the tissue or clitoris; and selecting a component of said sensitizing agent from the group consisting of: Peppermint oil, Cornmint oil, Eucalypius ul, C...one.la o:1 Indian ;urpentie oi, Camphor nil Cinnamon oils.

Salicylate, capsiatin, and oil soluble vitamins (co-enzymes) of A, D, or E. The steps may include placing the sensitizing agent in a reservoir of an applicator; arranging a cover on the applicator to protect the agent in the reservoir. The WO 01/45599 PCT/US00/33987 10 applicator may include a brush. The applicator may include a roller at one end thereof. The applicator may include a sponge at one end thereof. The sensitizing agent comprises a semi-solid stick having a notch on a distal end thereof to facilitate application of the agent to the tissue such as a clitoris.

Further unique properties of a combination menthol/L-arginine topical clitoral sensitizing preparation provides the basis of the present invention.

Sequential application first by menthol applied topically to the mucous membrane of the clitoris has an almost immediate response by affecting vasodilation and blood engorgement warmth (via the thermoreceptors). The duration of menthol's action on mucous membranes may be for fifteen-to-twenty minutes. Subsequent topical application of L-arginine utilizes its topical or systemic effect, via the NOS synthase/NO system, to create corpus cavernosa engorgement, which has a delayed onset of action from between fifteen to twenty minutes. By combining the two compounds, with simultaneous topical application of menthol and L-argininc, their effect would be immediate and prolonged because of their two different, but related, methods of action.

L-arginine absorption is promoted by the actions of menthol. Eccles reports studies by Katayama (1972), Morimoto (1993) and Yamo (1991) where the topical application of menthol, because of its local vasodilatative and lipidphillic properties, promotes the penetration of other topical drug preparation applied concurrently with menthol. These studies found rapid absorption of indomethacin, cortisone, morphine hydrochloride, and methyl salicylate when applied topically in combination with menthol. It is only rational that the absorption of L-arginine by the mucous membrane is hastened when applied in combination with menthol. This is a direct action of the lipidphillic and vasodilation properties of menthol. The action of menthol causes the L-arginine NOS/NO vasodilation to be effective within minutes of the topical application of the menthol/L-arginine combination.

A different effect is realized on the clitoris and the penis using the same menthoi/L-arginie combination. This is because the integu ment of the clitoris is non-keratinized epithelium, a 1% menthol and 2% L-arginine preparation, topically applied, is immediately absorbed, and immediately active in sensitizing the clitoris. The penis is relatively unaffected by the application of the same strength WO 01/45599 PCT/US00/33987 11 cream because the external epithelium is keratinized squamous epithelium. The keratinized squamous epithelium, by nature of the keratin, acts as a barrier to the absorption of the preparation. Therefore, the same preparation of 1% menthol and 2% L-arginine combination sensitizes the clitoris, without sensitizing the penis.

The invention thus comprises a topical compound preparation of sensitizing cream for application to the non-keratinized epithelium of a female, comprising a preparation of L-arginine, and a preparation of menthol. The preparation of L-arginine may have a concentration of 4% or less. The preparation of menthol may have a concentration of 5% or less. The preparation of L-arginine may in one embodiment have a concentration of 2% and the preparation of menthol may have a concentration of 1%.

The compound preparation may in one embodiment be enclosed within a reservoir of an applicator. The reservoir may have multiple chambers.

The reservoir may have an arrangement of conduits from the reservoir to an outer clitoral-touching surface on the applicator. The invention also includes a method of sensitizing the non-keratinized epithelium of a female, comprising the steps of: applying a preparation of menthol and L-arginine to the epithelium, arranging the preparation of L-arginine in a concentration of less than and arranging the preparation of menthol in a concentration of less than The method may include the step of: placing the preparations of menthol and L-arginine in an applicator reservoir for distribution onto the epithelium, and may include the step of applying the preparations to the epithelium in a sequential manner.

Brief Description of the Drawings Figure 1 is a front elevational view of a solid compound single-use applicator; Figure 2 is a view taken along the lines 2-2 of Figure 1; Figure 3 is a front elevational view of a solid compound multiple-use applicator; Figure 4 is a view taken along the lines 4-4 of Figure 3; Figure 5 is a front elevational view of a gel/cream/liquid compound single-use applicator; Figure 6 is a front elevational view of a gel/cream/liquid compound WO 01/45599 PCTUS00/33987 12 single or multiple use brush applicator; Figure 7 is a view of the applicator shown in Figure 6, with its cap off; Figure 8 is a side elevational view, in section, of the applicator cap shown in Figure 6; Figure 9 is front elevational view of a gel/cream or liquid applicator with roller balls; Figure 10 is a view taken along the lines 10-10 of Figure 9; and Figure 11 is a perspective view of a further applicator of the present invention.

Description of Preferred Embodiments Referring now to the invention and the drawings in detail, alternate preparations of menthol and related cooling compounds comprises a class of single-source of botanical or essential oils that can be used individually or as a combination of several oils such as: Peppermint oil; Commint oil; Eucalyptus oil; Citronella oil; Indian turpentine oil; Camphor oil and Cinnamon oils, as compounds of the present invention. Any of these referenced oils could evoke the menthol-like effect on the mucous membrane to facilitate or promote the topical absorption of L-arginine. Salicylate and capsiatin, two commonly used minor skin irritants and oil soluble vitamins (co-cnzymes) A, D, or E, could also potentiate absorption of menthol, L-arginine, minor skin irritants, or any of the menthol-related cooling compounds. The oil soluble vitamins could be used to substitute for, or be used in addition to, any of the previously listed components in a topical tissue or clitoral sensitizing preparation. Such solid/liquid state dynamics for the topical delivery of tissue or clitoral sensitizing compounds which cover any of the potential compounds for topical application to sensitize the tissue of lips or the clitoris because they can have different solid/liquid states at ambient and at body temperatures.

A gel/cream or liquid compound could be directly applied to the tissue ui clitoris foropical aborpo L the solid -sta. compound, the gel/cream must liquefy before absorption can be effected. The dynamics of how rapidly a compound transforms from a solid state or gel/cream state to a liquid state could be controlled to evoke an almost immediate effect, or a relatively delayed WO 01145599 PCT/USOO/33987 13 effect, before absorption of the compound.

A crystalline related dissolution may be different from the temperature related dissolution of a solid or a gel/cream. Small crystals of menthol, L-arginine, or any of the previously described components, may be suspended in a base vehicle. Their availability for absorption would depend on their dissolution from a crystalline state to a liquid state. The crystalline effect may be designed to control the rate of absorption: for instance, whether the compound were available for absorption immediately on application, or if a delayed, sustained absorption over a period of time were desired. Both of these parameters could allow the discrete, private application of the clitoral-sensitizing compound in anticipation of intercourse, without knowledge of the partner.

A single use or a multiple use delivery systems comprising a tissue or clitoral-sensitizing preparation 10 may be individually packaged within a small tube 12 or packet 14 for single use, as shown in Figures 1, 2 and 5. The tube 12 may be gripped by the thumb and first finger, and the compound preparation thereon applied as desired.

The packet 14 shown in Figure 5 has a break-away seal 15 which permits the gel/cream or liquid 10 therein to be readily applied by merely squeezing the packet 14. Conversely, a multiple-dose reusable delivery system, like a tube of hand cream or toothpaste, or a stick of semi-solid compound, tissue such as lips or clitoral-sensitizing balm 16, may be packaged for personal use, as shown by the "lipstick-like" rotatively adjustable applicators 18 in Figures 3 and 4. This adjustable applicator 18 has a cap 20 to cover the balm compound 16.

The apparatus and methods to deliver a topical preparation to the tissue such as lips or clitoris may also be comprised of a solid or semi-solid compound that may be directly applied to the lips of the mouth or the undercarriage of the clitoris regardless of the use of a single-or multiple-use delivery system. The clitoral contact area of the solid or semi-solid compound in one preferred _e.bodi.nt i a notch to incrPazP. the. mirface area and clitoral contact of the compound 16, as shown in Figures 1 and 3. The notch is arranged with a height of 0.5 to 2 centimeters, and a maximum width of 2 centimeters at the rim of the notch A properly designed concave notch will topically apply the WO 01/45599 PCT/US00/33987 14compound 16 to the 180 degree undercarriage of the clitoris. With proper directions for use, the application surface will initially contact the vestibular tissue at the base of the clitoris, to spread the compound on the entire clitoris. A gel/cream or liquid compound 30 of the present invention would be applied to the clitoris with the same motions, but would require a different type of application device. The gel/cream or liquid compound 30 may be applied by "roller balls" 32 like those used to apply viscous deodorants, as shown in Figures 9 and 10, supported within a foraminous top 34, covered when not needed, by a cap 46. The gel/cream or liquid compound may also be applied by a sponge or brush 40 secured to a top 42 in a reservoir 44, as shown in Figures 6 and 7. A cap 48, shown also in Figure 8 may include a removable seal 50, both of which are arranged to be removable to expose the sponge or brush 40 and openings 46 in the reservoir 44 to supply the fluid compound thereto. Any of the delivery devices for gel/cream or liquids could be designed to increase the surface area of the applicator tip and generally use the concave notch described for the solid compounds. The gel/cream and liquid applicators would have either a single-use reservoir or a multi-use reservoir. All of the delivery devices would have a cap that would seal the device before the initial use, and protect the applicator tip from contamination before use. Multi-use devices, such as shown in Figures 3, 4, 6, 7 and 9 would have the resealing cap 48 for their protection.

The present invention also utilizes the unique properties of a combination menthol/L-arginine topical clitoral sensitizing preparation. In one embodiment, a sequential application first by menthol applied topically to the mucous membrane of the clitoris has an almost immediate response by affecting vasodilation and blood engorgement warmth (via the thermoreceptors). The duration of menthol's action on mucous membranes may be for fifteen-to-twenty minutes. Subsequent topical application of L-arginine utilizes its topical or systemic effect, via the NOS synthase/NO system, to create corpus cavernosa engorgement, ,hich has a de!ayed onset of action from between fifteen to twenty minutes. Such a sequential delivery of multiple preparations may be accomplished by an applicator 110, as shown in Figure 10. The applicator 110 may have a plurality of reservoirs 112 and 114, each with their own conduits 116 and 118 between the reservoirs 112 and 114 and a clitoral engaging surface 120. Each preparation of menthol and L-arginine may have their own rate of distribution, to provide the sequential application to the treatment situs.

In a further embodiment, a common reservoir 122 may be arranged within the applicator 110. By combining the two compounds within that common reservoir 122 as a simultaneous topical application of menthol and L-arginine together, their effect would be immediate and prolonged because of their two different, but related methods of action.

Such a range of L-arginine of less than 4% concentration and a range of menthol of less than 5% concentration is preferred in an application, either with the distribution via an applicator 110, or by other topical application.

Where the terms "comprise", "comprises", "comprised" or "comprising" are used in this specification, they are to be interpreted as specifying the presence of the stated features, integers, steps or components referred to, but not to preclude the presence or S" addition of one or more other feature, integer, step, component or group thereof O 0S 2106/02,1dl2780.oomdoc.15

Claims (21)

1. 2. The topical compound preparation of sensitizing cream for application to the non-keratinized epithelium of a female, as recited in claim 1, wherein said preparation of L-arginine has a concentration of 4% or less.
2. 3. The topical compound preparation of sensitizing cream for application to the non-keratinized epithelium of a female, as recited in claim I or 2, wherein said :preparation of menthol has a concentration of 5% or less.
3. 4. The topical compound preparation of sensitizing cream for application to S the non-keratinized epithelium of a female, as recited in claims 1, 2 or 3, wherein said preparation of L-arginine has a concentration of 2% and said preparation of menthol has a concentration of 1%. 20 0
4. 5. The topical compound preparation of sensitizing cream for application to the non-keratinized epithelium of a female, as recited in any one of the preceding claims, wherein said compound preparation is enclosed within a reservoir of an applicator. 25 6. The topical compound preparation of sensitizing cream for application to the non-keratinized epithelium of a female, as recited in claim 5, wherein said reservoir has multiple chambers.
5. 7. The topical compound preparation cf sensitizing cream for application to the non-keratinized epithelium of a female, as recited in claim 5, wherein said reservoir has an arrangement of conduits from said reservoir to an outer clitoral touching surface on said applicator. 3010S/05.S I 27ROcliims. 16 COMS ID No: SBMI-01272011 Received by IP Australia: Time 14:32 Date 2005-05-30 30/05 '05 14:29 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AUS PATENT OFFICE 1005
6. 17- 8. A method of sensitizing the non-keratinized epitheium of a fema l, such method including the step of: applying the topical compound preparation of any one of claims 1 to 4 to said epithelium. 9. The method of sensitizing the non-keratinized epithelium of a female, as recited in claim 8, including the step of: placing said preparations of menthol and L-arginine in an applicator reservoir for distribution onto said epithelium. The method of sensitizing the non-keratinized epithelium of a female, as recited in claim 8, including the step of: applying said preparations to the epithelium in a sequential manner. 15 11. A hand-manipulative applicator containing a composition, including a reservoir, said composition being a topical compound preparation as claimed in any one of claims 1 to 4; and an opening in the reservoir to permit exposure of said composition. 12. The hand manipulable applicator containing a composition of claim 11, wherein the composition is a gel. *13. The hand manipulable applicator containing a composition of claim 11, 25 wherein the composition is a semi-solid. 14. The hand manipulable applicator containing a composition of claim 11, wherein the composition is a cream. 15. The hand manipulable applicator containing a composition of claim 11, wherein the composition is a liquid. 16. .The hand manipulable applicator containing a composition of claim 11, further including an applicator sponge. 30/5/05,w 1l27 0ollIms,17 COMS ID No: SBMI-01272011 Received by IP Australia: Time 14:32 Date 2005-05-30 30/05 '05 14:29 FAX 81 3 9859 1588 CALLINAN LAWRIE MELB AUS PATENT OFFICE 1A006 -18- 17. The hand manipulable applicator containing a composition of claim 11, further including an applicator brush.
7. 18. The hand manipulable applicator containing a composition of claim 11, further including an applicator roller ball.
8. 19. The hand manipulable applicator containing a composition of claim 11, wherein the composition further includes a compound selected from the group consisting of peppermint oil, cornmint oil, eucalyptus oil, citronella oil, Indian turpentine oil, camphor oil, vitamin A, vitamin D, vitamin E, Salicylate, capsiatin, and cinnamon oil. The hand manipulable applicator containing a composition of claim 11, wherein the concentration of menthol in the composition is less than 4%. S
9. 21. The hand manipulable applicator containing a composition of claim 11, wherein the concentration of L-arginine in the composition is less than 2%.
10. 22. The hand manipulable applicator containing a composition of claim 11, 20 wherein the concentration of L-arginine in the composition is 1%.
11. 23.' A method for the preparation of composition for applying to clitoral or lip tissue, said method including the step of admixing menthol and L-arginine having a concentration of 1% to 10% in a carrier to form a composition.
12. 24. A method for the preparation of a composition for applying to clitoral or lip tissue to cause vasodilatation, said method including the step of admixing menthol and L-arginine having a concentration of 1% to 10% in a carrier to form a composition.
13. 25. The method of claim 23, or 24, further including admixing a compound selected from the group consisting of peppermint oil, cornmint oil, eucalyptus oil, citronella oil, Indian turpentine oil, camphor oil, vitamin A, vitamin D, vitamin E, salicylate, capsiatin, and cinnamon oil with the L-arginine and menthol. 30/05/05,sw 127A0claims. I COMS ID No: SBMI-01272011 Received by IP Australia: Time 14:32 Date 2005-05-30 30/05 '05 14:30 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AUS -4 PATENT OFFICE [1007 19-
14. 26. The method of claim 23 or 24, wherein the composition includes less than 4% L-arginine.
15. 27. The method of claim 23 or 24, wherein the composition includes less than 2% L-arginine.
16. 28. The method of claim 23 or 24, wherein the composition includes less than 5% menthol. t0
17. 29. A method for causing vasodilatation of clitoral or lip tissue, the method including the step of administering to a non-keratinized portion of the clitoral or lip tissue a composition including L-arginine having a concentration of 1% to 10% and menthol.
18. 30. A method for causing vasodilatation of clitoral or lip tissue, the method 15 including the step of sequentially administering to a non-keratinized portion of the clitoral or lip tissue a composition including menthol and a composition comprising L-arginine. S31. A hand-manipulable, tissue stimulant-applying applicator for use to apply a tissue stimulating compound to the sensitive area of the lips or the clitoris of a human 20 female, including: a reservoir for containment of a tissue stimulating compound; said tissue stimulating compound being said topical compound preparation as :claimed in any one of claims 1 to 4 disposed in said reservoir; and a removable portion on said reservoir to permit exposure of said compound to 25 permit said compound to be applied topically.
19. 32. The hand-manipulable, tissue stimulant-applying applicator as recited in claim 31, wherein said portion includes a removable cap. 31. The hand-manipulable, tissue stimulant-applying applicator as recited in claim 31, wherein said reservoir includes a tube and said portion.
20. 34. The hand-manipulable, tissue stimulant-applying applicator as recited in claim 31, wherein said compound comprises a gel.
21. 30105105.w12780cliims,19 COMS ID No: SBMI-01272011 Received by IP Australia: Time 14:32 Date 2005-05-30 30/05 '05 14:30 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AUS PATENT OFFICE Q)008 The hand-manipulable, tissue stimulant-applying applicator as recited in claim 31, .wherei said compound comprises a cream. S36. The hand-manipulable, tissue stimulant-applying applicator as recited in claim 31, wherein said compound comprises a fluid liquid. 37. The hand-manipulable, tissue stimulant-applying applicator as recited in claim 31, wherein said compound comprises a semi-solid. 38. The hand-manipulable, tissue stimulant-applying applicator as recited in claim 37, wherein said semi-solid compound has a notch on its distalmost end to facilitate the application of said compound. 15 39. The hand-manipulable, tissue stimulant-applying applicator as recited in o* claim 36, wherein said applicator includes a brush thereon. 40. The hand-manipulable, tissue stimulant-applying applicator as recited in claim 36, wherein said applicator includes a sponge thereon. 41. The hand-manipulable, tissue stimulant-applying applicator as recited in .claim 36, wherein said applicator includes a roller ball arrangement thereon. 42. The hand-manipulable, tissue stimulant-applying applicator as recited in 25 claim 31, wherein said compound comprises a mixture of menthol and L-arginine. Dated this 30 t h day of May, 2005 By Their Patent Attorneys CALLINAN LAWRIE .sw l 1780ci Ima.,O COMS ID No: SBMI-01272011 Received by IP Australia: Time 14:32 Date 2005-05-30